Thrombin Generation Mediators and Markers in Sepsis Associated Coagulopathy and Their Modulation by Recombinant Thrombomodulin

Abstract 1131

Severe sepsis remains the most common cause of death in critically ill patients and thrombin plays a crucial role in the pathogenesis of sepsis associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin antithrombin complex (TAT) and d-Dimer (DD) throughout the course of hospital stay in subjects identified with sepsis. Plasma samples from seven hundred and fifty eight patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized controlled trial, separated into treatment and placebo groups were analyzed for various parameters using ELISA methods. Plasma levels of F1.2, DD, and TAT were recorded at several time points following administration of recombinant thrombomodulin or placebo and the results are tabulated as the median values, in the following tables. All parameters in both treatment groups showed a decrease from the baseline values at day 14. In the group treated with thrombomodulin the median F1.2 levels demonstrated a marked decrease on day 14 exhibiting a 50% decrease, whereas the F1.2 levels fluctuated throughout the study period and showed slight change on day 14, in the placebo group. Although both groups showed a gradual decrease in the DD, the group treated with thrombomodulin demonstrated a stronger decrease over the 14 day period compared to the placebo treated group. While the data was widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through such targets as DD, F1.2 and TAT may play an important regulatory role in the pathogenesis of sepsis associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin down regulates the thrombin generation mediators/markers in sepsis associated DIC.